8VYX

Crystal Structure of the ER-alpha Ligand-binding Domain (L372S, L536S) in complex with k-410

これはPDB形式変換不可エントリーです。

8VYX の概要

• エントリーDOI: 10.2210/pdb8vyx/pdb
• 分子名称: Estrogen receptor, 4,4'-[(1S,4S,5R)-5-(3,4-dihydroquinoline-1(2H)-sulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl]diphenol (3 entities in total)
• 機能のキーワード: estrogen receptor, nuclear protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 112147.73

構造登録者

Min, C.K.,Nwachukwu, J.C.,Hou, Y.,Russo, R.J.,Papa, A.,Min, J.,Peng, R.,Kim, S.H.,Ziegler, Y.,Rangarajan, E.S.,Izard, T.,Katzenellenbogen, B.S.,Katzenellenbogen, J.A.,Nettles, K.W. (登録日: 2024-02-09, 公開日: 2024-06-12)

主引用文献

Min, C.K.,Nwachukwu, J.C.,Hou, Y.,Russo, R.J.,Papa, A.,Min, J.,Peng, R.,Kim, S.H.,Ziegler, Y.,Rangarajan, E.S.,Izard, T.,Katzenellenbogen, B.S.,Katzenellenbogen, J.A.,Nettles, K.W.
Asymmetric allostery in estrogen receptor-alpha homodimers drives responses to the ensemble of estrogens in the hormonal milieu.
Proc.Natl.Acad.Sci.USA, 121:e2321344121-e2321344121, 2024

PubMed Abstract: The estrogen receptor-α (ER) is thought to function only as a homodimer but responds to a variety of environmental, metazoan, and therapeutic estrogens at subsaturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations-receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining the binding of the same ligand in crystal structures of ER in the agonist vs. antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist vs. antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from the ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric vs. dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing different modes for ligand-dependent regulation of ER activity.

PubMed: 38830107
DOI: 10.1073/pnas.2321344121

実験手法

X-RAY DIFFRACTION (1.69 Å)